BR112017000127B1 - POLYMORPHIC FORM III OF N-[2-(6-FLUORO-1HINDOL-3-IL)ETHYL]-3-(2,2,3,3-TETRAFLUOROPROPOXY)BENZYLAMINE, PREPARATION PROCESSES, ITS PHARMACEUTICAL COMPOSITION AND ITS USE - Google Patents

Abstract

NEW POLYMORPHIC FORM OF N-[2-(6-FLUORO-1H-INDOL-3-IL) ETHYL]-3-(2,2,3,3-TETRAFLUOROPROPOXY)BENZYLAMINE HYDRODRATE FOR THE TREATMENT OF ALZHEIMER'S DISEASE. The present invention relates to a new polymorphic form of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride.

Description

AREA OF INVENTION

[0001] The present invention relates to a new polymorphic form of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy hydrochloride) )benzylamine.

FUNDAMENTALS OF THE INVENTION

[0002] The incidence of Alzheimer's disease is predicted to increase by the year 2050 with an estimated prevalence of 11 to 16 million cases. Currently, two classes of drugs have been approved by the FDA to control the symptoms of Alzheimer's disease - acetylcholinesterase inhibitors (AChEIs) and an N-methyl-D-aspartate19 (NMDA) receptor antagonist. AChEIs are commonly used as initial treatment after diagnosis. The AChEIs (donepezil, rivastigmine, galantamine, and tacrine) are indicated for mild to moderate Alzheimer's disease; only donepezil has been approved for the severe stage.

[0003] AChEIs are not helpful for all patients with Alzheimer's disease, and are even ineffective in many patients. Considering that AChEIs and memantine have only a modest symptomatic effect, and fail to prevent the decline caused by Alzheimer's disease and slow disease progression, there is a high unmet need for more effective symptomatic treatments and disease modification/slowing therapies. illness.

[0004] The use of selective 5-HT6 receptor antagonists has been suggested to treat cognitive dysfunction and is based on several lines of reasoning. For example, selective 5-HT6 receptor antagonists have been shown to modulate the function of cholinergic and glutamatergic neurons. The activity of selective 5-HT6 receptor antagonists has been demonstrated in animal models of cognitive function. Since the publication of the first selective 5-HT6 receptor antagonists, several reports have appeared on the activity of these selective compounds in in vivo models of cognitive function. N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine, CAS number 467458-02-2, (hereinafter also referred to as "Lu AE58054") is a 5-HT6 receptor antagonist and its chemical structure is illustrated below:

[0005] The synthesis of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine, its use for the treatment of disease disease and pharmaceutical compositions comprising that compound are disclosed in U.S. Patent No. 7,157,488 ("the '488 patent"). The '488 patent further describes the preparation of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride salt.

[0006] N-[2-(6-Fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine can be produced according to the method described in WO 11/76212.

[0007] Using the methods in the '488 patent and in WO 11/76212, N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2) hydrochloride is obtained ,3,3-tetrafluoropropoxy)benzylamine in the form of a solid.

[0008] Pharmaceutical solids can exist in amorphous, glassy or crystalline states. Furthermore, crystalline materials can be found in the form of hydrates or other solvates. If such a compound can exist in more than one crystal arrangement (polymorphic form), the compound is said to exhibit polymorphism.

[0009] In order to be able to provide an active pharmaceutical ingredient of high and reproducible quality, and with well-defined biological activity, it is desirable to have the active pharmaceutical ingredient in the most thermodynamically stable form.

[0010] The inventors of the present invention have discovered a new and thermodynamically stable form of the hydrochloride salt of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3 -tetrafluoropropoxy)benzylamine.

SUMMARY OF THE INVENTION

[0011] The present invention relates to the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy) hydrochloride benzylamine.

[0012] The invention additionally relates to a process for preparing the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3) hydrochloride ,3-tetrafluoropropoxy)benzylamine comprising: a. capturing the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride from a hydrochloride suspension of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine in an organic solvent selected from the list of acetonitrile, propionitrile, acetone, methanol, ethanol, toluene and xylenes (ortho, meta or para) or a mixture thereof, at a temperature below 60 °C.

[0013] The invention additionally relates to a process for preparing the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3) hydrochloride ,3-tetrafluoropropoxy)benzylamine comprising: a. add polymorphic form I, polymorphic form II, amorphous form or a mixture of forms of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2, 3,3-tetrafluoropropoxy)benzylamine to an organic solvent selected from the list of acetonitrile, propionitrile, acetone, methanol, ethanol, toluene and xylenes (ortho, meta or para) or a mixture thereof, at a temperature below 60 °C to produce a suspension; B. capturing the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride.

[0014] The invention additionally relates to a process for preparing the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3) hydrochloride ,3-tetrafluoropropoxy)benzylamine comprising: a. seed a suspension of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride in an organic solvent selected from the list of acetonitrile , propionitrile, acetone, methanol, ethanol, toluene and xylenes (ortho, meta or para) or a mixture thereof, at a temperature below 60 °C, with the polymorphic form III of N-[2-(6-fluoro) hydrochloride -1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine; B. capturing the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride.

[0015] The invention additionally relates to a process for preparing the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3) hydrochloride ,3-tetrafluoropropoxy)benzylamine comprising: a. add polymorphic form I, polymorphic form II, amorphous form or a mixture of forms of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2, 3,3-tetrafluoropropoxy)benzylamine to an organic solvent selected from the list of acetonitrile, propionitrile, acetone, methanol, ethanol, heptane, toluene and xylenes (ortho, meta or para) or a mixture thereof, at a temperature below 60 °C to produce a suspension; B. seed with polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride at a temperature below 60°C °C; w. capturing the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride.

[0016] The invention further relates to the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy) hydrochloride benzylamine for use as a medicament, to a pharmaceutical composition comprising polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3 hydrochloride) -tetrafluoropropoxy)benzylamine and to a method of treating Alzheimer's disease as adjunctive therapy to acetylcholinesterase targeted treatment comprising administering an effective daily dose of polymorphic form III of N-[2-(6-fluoro-1H-indole-3 hydrochloride) -yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine to a patient in need of such treatment.

BRIEF DESCRIPTION OF THE FIGURES

[0017] FIGURE 1: X-ray powder diffractogram of the polymorphic form I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3 hydrochloride) - tetrafluoropropoxy)benzylamine.

[0018] FIGURE 2: Powder X-ray diffractogram calculated from the crystalline structure of the polymorphic form I.

[0019] FIGURE 3: X-ray powder diffractogram of the polymorphic form II of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3 hydrochloride) - tetrafluoropropoxy)benzylamine.

[0020] FIGURE 4: Powder X-ray diffractogram calculated from the crystalline structure of the polymorphic form II.

[0021] FIGURE 5: X-ray powder diffractogram of the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3 hydrochloride) - tetrafluoropropoxy)benzylamine.

[0022] FIGURE 6: Shows the crystalline packing of polymorphic forms I and II of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3 hydrochloride) - tetrafluoropropoxy)benzylamine.

[0023] FIGURE 7: X-ray powder diffractograms of polymorphic form III (lower curve) and a mixture of polymorphic form III and polymorphic form IV (upper curve).

[0024] FIGURE 8: FTIR spectrum of polymorphic form III.

[0025] FIGURE 9: FTIR spectrum of polymorphic form I.

[0026] FIGURE 10: FTIR spectra of two batches of the polymorphic form III shown in the spectral region 1130 to 1050 cm-1.

[0027] FIGURE 11: Two-batch FTIR spectra of polymorphic form III (marked with "III") and a spectrum of polymorphic form I (marked with "I") shown in the spectral region 1130 to 1050 cm-1.

DETAILED DESCRIPTION OF THE INVENTION

[0028] Prior to the present invention, two polymorphic modifications of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy) hydrochloride were known benzylamine. Polymorphic form I which is found to be the thermodynamically stable form at low temperature (less than about 60°C) and polymorphic form II which is the thermodynamically stable form at high temperature (greater than about 60°C) . Polymorph form II has a melting point, as determined by Differential Scanning Calorimetry (DSC) at 171°C. Polymorph form I transforms into polymorph form II upon heating in the temperature range of 120 to 140 °C, therefore it was not possible to determine a melting point for polymorph form I. The crystal structures of the two polymorph forms were determined using analysis single-crystal X-ray. Structural parameters are provided in table 1 below: Table 1 - Structural parameters of polymorphic forms I and II of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride.

[0029] The crystalline packing differs significantly between the two polymorphic forms (Figure 6).

[0030] Crystallization experiments were carried out in search of other polymorphic modifications, but without success. All experiments resulted in polymorphic form I and polymorphic form II, depending on the temperature. It was therefore surprising to discover a new and thermodynamically more stable form which, based on DSC, is very similar to polymorphic form I (also transforms into polymorphic form II upon heating in the temperature range of 120 °C to 140 °C) and has many low-angle reflections in common with the polymorphic shape I in an X-ray powder diffractogram (XRPD), but also differs significantly in other reflections.

[0031] Despite previous unsuccessful efforts to find new polymorphic forms of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy hydrochloride )benzylamine, the inventors of the present invention have found a way to produce a new polymorphic form of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3, 3-tetrafluoropropoxy)benzylamine, referred to herein as the polymorphic form III.

[0032] It was found that in the temperature range in which the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3, 3-tetrafluoropropoxy)benzylamine is the thermodynamically stable polymorphic form, it is easier to produce polymorphic forms I and II of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2) hydrochloride ,2,3,3-tetrafluoropropoxy)benzylamine. In summary, polymorphic forms I and II of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride have an advantage kinetics on the polymorphic form III which is the thermodynamically stable form making this polymorphic form more difficult to produce.

[0033] The polymorphic form III is particularly advantageous in terms of being the most thermodynamically stable form of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2, 3,3-tetrafluoropropoxy)benzylamine.

[0034] The present invention is further described in embodiments 1 to 42 (M(1) to M(42)) below:

[0035] M(1): Polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride.

[0036] M(2): The polymorphic form according to (M1) characterized by an X-ray powder diffractogram showing peaks at the following 2θ angles: 4.63°, 6.94°, 13.89°, 17, 26° and 19.97°.

[0037] M(3): The polymorphic form according to (M2) further characterized by an X-ray powder diffractogram showing peaks at the following 2θ angles: 4.63°, 6.94°, 13.89°, 17 .26°, 18.95°, 19.97°, 22.53° and 23.65°.

[0038] M(4): The polymorphic form according to (M3) further characterized by an X-ray powder diffractogram showing peaks at the following 2θ angles: 4.63°, 6.94°, 13.89°, 17 .26°, 18.07°, 18.49°, 18.95°, 19.47°, 19.97°, 20.53°, 21.83°, 22.53°, 23.27°, 23 .65° and 28.91°.

[0039] M(5): The polymorphic form according to (M1), wherein said compound exhibits an X-ray powder diffractogram as shown in figure 5.

[0040] M(6): A process for preparing the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3 hydrochloride) - tetrafluoropropoxy)benzylamine comprising: capturing the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride to starting from a suspension of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride in an organic solvent selected from the list of acetonitrile, propionitrile, acetone, methanol, ethanol, toluene and xylenes (ortho, meta or para) or a mixture thereof, at a temperature below 60 °C.

[0041] M(7): A process for preparing the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3 hydrochloride) - tetrafluoropropoxy)benzylamine comprising: a) adding polymorphic form I, polymorphic form II, amorphous form or a mixture of forms of N-[2-(6-fluoro-1H-indol-3-yl)ethyl] hydrochloride -3-(2,2,3,3-tetrafluoropropoxy)benzylamine to an organic solvent selected from the list of acetonitrile, propionitrile, acetone, methanol, ethanol, toluene and xylenes (ortho, meta or para) or a mixture thereof, to a temperature less than 60°C to produce a suspension; b) capturing the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride.

[0042] M(8): A process for preparing the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3 hydrochloride) - tetrafluoropropoxy)benzylamine comprising: a) seeding a suspension of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride in an organic solvent selected from the list of acetonitrile, propionitrile, acetone, methanol, ethanol, toluene and xylenes (ortho, meta or para) or a mixture thereof, at a temperature below 60 °C, with the polymorphic form III of N hydrochloride -[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine; b) capturing the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride.

[0043] M(9): A process for preparing the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3 hydrochloride) - tetrafluoropropoxy)benzylamine comprising: a) adding polymorphic form I, polymorphic form II, amorphous form or a mixture of forms of N-[2-(6-fluoro-1H-indol-3-yl)ethyl] hydrochloride -3-(2,2,3,3-tetrafluoropropoxy)benzylamine to an organic solvent selected from the list of acetonitrile, propionitrile, acetone, methanol, ethanol, heptane, toluene and xylenes (ortho, meta or para) or a mixture thereof, at a temperature below 60°C to produce a suspension; b) seeding with polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride at a lower temperature at 60°C; c) capturing the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride.

[0044] M(10): The process according to any one of (M6) to (M9), wherein the mixture of organic solvents is such that crystallization takes place at a temperature below 60 °C.

[0045] M(11): The process according to any one of (M6) to (M9), wherein the organic solvent is a mixture of acetone and heptane in the ratio of 1:4.

[0046] M(12): The process according to any one of (M6) to (M9), wherein the organic solvent is a mixture of methanol and toluene in the ratio of 1:4.

[0047] M(13): A compound according to any one of (M1) to (M5) for use as a medicament.

[0048] M(14): A pharmaceutical composition comprising a compound according to any one of (M1) to (M5).

[0049] M(15): The pharmaceutical formulation according to (M14) comprising pharmaceutically acceptable carriers or diluents.

[0050] M(16): A method of treating Alzheimer's disease as adjunctive therapy to acetylcholinesterase targeted treatment comprising administering an effective daily dose of a compound according to any one of (M1) to (M5) to a patient who needs such treatment.

[0051] M(17): The method according to M(16), wherein the effective daily dose administered to the patient of said compound is between about 5 and about 120 mg.

[0052] M(18): The method according to (M16), wherein the effective daily dose administered to the patient of said compound is between about 30 and about 60 mg.

[0053] M(19): The method according to any one of (M16) to (M18), wherein the acetylcholinesterase inhibitor is donepezil.

[0054] M(20): The method according to any one of (M16) to (M18), wherein the acetylcholinesterase inhibitor is rivastigmine.

[0055] M(21): The method according to any one of (M16) to (M18), wherein the acetylcholinesterase inhibitor is galantamine.

[0056] M(22): The method according to any one of (M16) to (M18), wherein the acetylcholinesterase inhibitor is tacrine.

[0057] M(23): A method of treating a disease or disorder selected from dementia in Parkinson's disease, Huntington's chorea and Down syndrome comprising administering an effective daily dose of a compound according to any one of (M1 ) to (M5) to a patient who needs such treatment.

[0058] M(24): A method of treating a disease or a disorder selected from cognitive disorders, age-related cognitive disorder, mild cognitive impairment, mood disorders (including depression, mania, bipolar disorders), psychosis (in particular schizophrenia), anxiety, panic disorder with or without agoraphobia, agoraphobia without a history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder and other unspecified anxiety disorder (particularly including generalized anxiety disorder, panic disorder and obsessive-compulsive disorder), idiopathic and induced Parkinson's disease by drugs, epilepsy, seizures, migraine (including migraine headache), withdrawal (including from substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), sleep disorders ( including narcolepsy), attention-deficit/hyperactivity disorder, conduct disorder, learning disorders, dementia (including Alzheimer's disease and AIDS-induced dementia), Huntington's chorea, cognitive deficits subsequent to cardiac surgery and bypass grafting saphenous vein, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, vascular dementia, multi-infarct dementia, amyotrophic lateral sclerosis and multiple sclerosis comprising administering an effective daily dose of a compound of according to any one of (M1) to (M5) to a patient in need of such treatment.

[0059] M(25): A compound according to any one of (M1) to (M5) for use in the treatment of Alzheimer's disease as adjunctive therapy to acetylcholinesterase targeted treatment.

[0060] M(26): The compound according to (M25), wherein the dose of said compound is between about 5 and about 120 mg.

[0061] M(27): The compound according to (M25), wherein the dose of said compound is between about 30 and about 60 mg.

[0062] M(28): The compound according to any one of (M25) to (M27), wherein the acetylcholinesterase inhibitor is donepezil.

[0063] M(29): The compound according to any one of (M25) to (M27), wherein the acetylcholinesterase inhibitor is rivastigmine.

[0064] M(30): The compound according to any one of (M25) to (M27), wherein the acetylcholinesterase inhibitor is galanthamine.

[0065] M(31): The compound according to any one of (M25) to (M27), wherein the acetylcholinesterase inhibitor is tacrine.

[0066] M(32): The compound according to any one of (M1) to (M5) for use in the treatment of a disease or disorder selected from dementia in Parkinson's disease, Huntington's chorea and Down's syndrome.

[0067] M(33): A compound according to any one of (M1) to (M5) for use in the treatment of a disease or a disorder selected from cognitive disorders, age-related cognitive disorder, mild cognitive impairment, mood disorders mood (including depression, mania, bipolar disorders), psychosis (in particular schizophrenia), anxiety, panic disorder with or without agoraphobia, agoraphobia without a history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder, and other unspecified anxiety disorder (particularly including generalized anxiety disorder, panic and obsessive-compulsive disorder), idiopathic and drug-induced Parkinson's disease, epilepsy, seizures, migraine (including migraine headache), withdrawal (including from substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines , cocaine, sedatives, hypnotics, etc.), sleep disorders (including narcolepsy), attention deficit/hyperactivity disorder, conduct disorder, learning disorders, dementia (including Alzheimer's disease and AIDS-induced dementia), Huntington's chorea, cognitive deficits subsequent to cardiac surgery and bypass grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, vascular dementia, multi-infarct dementia, sclerosis amyotrophic lateralis and multiple sclerosis.

[0068] M(34): Use of a compound according to any one of (M1) to (M5) for the manufacture of a medicament for the treatment of Alzheimer's disease as adjunctive therapy to treatment directed at acetylcholinesterase.

[0069] M(35): The use according to (M34), wherein the dose of said compound is between about 5 and about 120 mg.

[0070] M(36): The use according to (M34), wherein the dose of said compound is between about 30 and about 60 mg.

[0071] M(37): The use according to any one of (M34) to (M36), wherein the acetylcholinesterase inhibitor is donepezil.

[0072] M(38): The use according to any one of (M34) to (M36), wherein the acetylcholinesterase inhibitor is rivastigmine.

[0073] M(39): The use according to any one of (M34) to (M36), wherein the acetylcholinesterase inhibitor is galantamine.

[0074] M(40): The use according to any one of (M34) to (M36), wherein the acetylcholinesterase inhibitor is tacrine.

[0075] M(41): Use of a compound according to any one of (M1) to (M5) for the manufacture of a medicament for the treatment of a disease or disorder selected from dementia in Parkinson's disease, chorea Huntington's and Down syndrome.

[0076] M(42): Use of a compound according to any one of (M1) to (M5) for the manufacture of a medicament for the treatment of a disease or disorder selected from cognitive disorders, age-related cognitive disorder , mild cognitive impairment, mood disorders (including depression, mania, bipolar disorders), psychosis (in particular schizophrenia), anxiety, panic disorder with or without agoraphobia, agoraphobia without a history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder, and other unspecified anxiety disorder (particularly including generalized anxiety disorder, panic disorder, and obsessive-compulsive disorder), idiopathic and drug-induced Parkinson's disease, epilepsy, seizures, migraine (including migraine headache), withdrawal (including from substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), sleep disorders (including narcolepsy), attention deficit/hyperactivity disorder, conduct disorder, learning disorders, dementia (including Alzheimer's disease and AIDS-induced dementia), Huntington's chorea, cognitive deficits subsequent to heart surgery and bypass grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, vascular dementia , multi-infarct dementia, amyotrophic lateral sclerosis and multiple sclerosis.

[0077] M(43): The process according to any one of (M6) to (M10), wherein the suspension is prepared at a temperature of about 50 °C, such as 45 to 55 °C.

[0078] M(44): The process according to any one of (M6) to (M10), wherein the suspension is prepared at a temperature below 50 °C.

[0079] M(45): The polymorphic form according to (M1) characterized by an FTIR spectrum that has a relatively strong band intensity at the following band positions [cm-1]: 3426, 1586, 1089, 762 and a shoulder at 1099 cm-1.

[0080] M(46): The polymorphic form according to (M1) characterized by an FTIR spectrum in the spectral region of 1130 to 1050 cm-1 as shown in figure 10.

[0081] M(47): A pharmaceutical composition prepared from the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3) hydrochloride ,3-tetrafluoropropoxy)benzylamine.

[0082] M(48): A pharmaceutical composition prepared from the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3) hydrochloride ,3-tetrafluoropropoxy)benzylamine characterized by an X-ray powder diffractogram showing peaks at the following 2θ angles: 4.63°, 6.94°, 13.89°, 17.26° and 19.97°.

[0083] M(49): A pharmaceutical composition prepared from the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3) hydrochloride ,3-tetrafluoropropoxy)benzylamine characterized by an X-ray powder diffractogram showing peaks at the following 2θ angles: 4.63°, 6.94°, 13.89°, 17.26°, 18.95°, 19.97° °, 22.53° and 23.65°.

[0084] M(50): A pharmaceutical composition prepared from the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3) hydrochloride ,3-tetrafluoropropoxy)benzylamine characterized by an X-ray powder diffractogram showing peaks at the following 2θ angles: 4.63°, 6.94°, 13.89°, 17.26°, 18.07°, 18.49 °, 18.95°, 19.47°, 19.97°, 20.53°, 21.83°, 22.53°, 23.27°, 23.65° and 28.91°.

[0085] M(51): A pharmaceutical composition prepared from the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3) hydrochloride ,3-tetrafluoropropoxy)benzylamine characterized by an X-ray powder diffractogram as shown in figure 5.

[0086] M(52): A pharmaceutical composition prepared from the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3) hydrochloride ,3-tetrafluoropropoxy)benzylamine characterized by an FTIR spectrum that has a strong band intensity at the following band positions [cm -1 ]: 3426, 1586, 1089, 762 and a shoulder at 1099 cm -1 .

[0087] M(53): A pharmaceutical composition prepared from the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3) hydrochloride ,3-tetrafluoropropoxy)benzylamine characterized by an FTIR spectrum in the spectral region of 1130 to 1050 cm-1 as shown in figure 10.

Definitions

[0088] N-[2-(6-Fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine is "Lu AE58054". Lu AE58054 is a 5-HT6 receptor antagonist and its chemical structure is illustrated below:

[0089] The polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride is characterized by a diffractogram X-ray powder (XRPD) showing peaks at the following 2θ angles: 4.63°, 6.94°, 13.89°, 17.26° and 19.97°, more specifically at the following 2θ angles: 4.63 °, 6.94°, 13.89°, 17.26°, 18.95°, 19.97°, 22.53° and 23.65° and even more specifically at the following 2θ angles: 4.63°, 6.94°, 13.89°, 17.26°, 18.07°, 18.49°, 18.95°, 19.47°, 19.97°, 20.53°, 21.83°, 22.53°, 23.27°, 23.65° and 28.91°.

[0090] The polymorphic form I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride is characterized by a diffractogram X-ray powder showing peaks at the following 2θ angles: 4.62°, 6.95°, 13.90°, 17.40°, 20.15°, and 24.97°.

[0091] The polymorphic form II of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride is characterized by a diffractogram X-ray powder showing peaks at the following 2θ angles: 4.29°, 8.56°, 12.84°, 15.34°, 17.92°, and 28.75°.

[0092] All XRPD data provided in this document are indicated as ± 0.10 (°2θ).

[0093] N-[2-(6-Fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride solids obtained by the methods in the '488 patent and in WO 11/76212 are polymorphic forms I and II.

[0094] A "therapeutically effective amount" of a compound as used herein means an amount sufficient to cure, alleviate or partially delay the clinical manifestations of a given disease and its complications in a therapeutic intervention comprising the administration of said compound. An amount adequate to achieve this is defined as "a therapeutically effective amount". Effective amounts for each purpose will depend on the severity of the illness or injury as well as the weight and general condition of the subject. It will be understood that determination of an appropriate dosage can be achieved using routine experimentation, by constructing a matrix of values and testing different points in the matrix, which is all within the ordinary skills of a trained physician.

[0095] The terms "treatment" and "treat" as used herein mean the management and care of a patient for the purpose of combating a pathology, such as a disease or disorder. The term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of the active compound to alleviate the symptoms or complications, to delay the progression of the disease, disorder or condition, to alleviate or alleviating the symptoms and complications, and/or to cure or eliminate the disease, disorder or pathology as well as to prevent the pathology, where prevention is to be understood as the management and care of a patient for the purpose of combating the disease, pathology or disorder and includes administration of the active compounds to prevent the onset of symptoms or complications. Nevertheless, prophylactic (preventive) and therapeutic (curative) treatments are two separate aspects of the invention. The patient to be treated is preferably a mammal, in particular a human being.

[0096] Typically, the treatment of the present invention will involve daily administration of the compounds of the present invention. This could involve daily administration or twice daily administration or even more frequent administration.

[0097] A "therapeutically effective dose" of polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy) hydrochloride benzylamine is an amount sufficient to provide a clear therapeutic benefit compared to clinically observed baseline signs and symptoms of Alzheimer's disease as measured by ADAS-cog, and Alzheimer's disease-related dementia treated in association with the combination therapy.

[0098] "Immediate release" is intended to include a conventional release, in which the release of the drug begins immediately after its administration. As used herein, the term "immediate release" includes dosage forms that allow the drug to dissolve in the gastrointestinal contents, without intending to delay or prolong drug dissolution or absorption. The aim is for the drug to be released quickly after administration, for example, so that it is possible to release at least 80% of the anti-dementia drug within about 30 minutes of starting dissolution in a dissolution test.

[0099] The term "acetylcholinesterase inhibitor" is known to those skilled in the art and includes compounds selected from the group consisting of donepezil, rivastigmine, galantamine and tacrine. FDA approved dosages of the acetylcholinesterase inhibitor are encompassed by the present invention. The methods, for example, cover dosages of donepezil shown to be effective in controlled clinical studies of treating mild to moderate Alzheimer's disease, either 5 mg or 10 mg given orally once daily. A daily oral dose of 23 mg of donepezil is also approved for the treatment of moderate to severe Alzheimer's disease.

[0100] The term "per day/daily" means a given continuous period of twenty-four (24) hours.

[0101] The term "dose" is used herein to mean the administration of polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2, 3,3-tetrafluoropropoxy)benzylamine in a dosage form to the patient being treated. In some embodiments, the dose is a single oral formulation. In some embodiments, the dose is formulated as a tablet, capsule, pill, or transdermal patch administered to the patient.

[0102] The term "effective daily dose" means the total amount of polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3 ,3-tetrafluoropropoxy)benzylamine administered to a patient requiring therapy within a continuous twenty-four (24) hour period. As a non-limiting example, used herein only to illustrate the meaning of the term, an effective daily dose of 90 mg shall mean and include administration of a single dose of 90 mg within a twenty-four hour period, administration of two doses of 45 mg each within a twenty-four hour period, and the administration of three doses of 30 mg each within a twenty-four hour period, and so on. By administering polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride in such a manner, i.e. , more than once in a twenty-four hour period, such administrations may be evenly spaced within the twenty-four hour period, or may even be administered concurrently or nearly simultaneously.

[0103] The term "dose range" as used herein refers to an upper and lower limit of an acceptable range of the specified amount of agent. Typically, a dose of the agent in any amount within the specified range can be administered to patients receiving treatment.

pharmaceutical compositions

[0104] In one embodiment, the present invention relates to a pharmaceutical composition comprising polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2) hydrochloride ,2,3,3-tetrafluoropropoxy)benzylamine.

[0105] In an additional embodiment, the present invention relates to a pharmaceutical formulation comprising the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-( 2,2,3,3-tetrafluoropropoxy)benzylamine and pharmaceutically acceptable carriers or diluents.

[0106] The present invention further provides a pharmaceutical composition comprising a therapeutically effective amount of polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2) hydrochloride ,3,3-tetrafluoropropoxy)benzylamine and, optionally, a pharmaceutically acceptable carrier or diluent. Polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride can be administered alone or in combination with pharmaceutically acceptable carriers, diluents or excipients, in single or multiple doses. Pharmaceutical compositions according to the invention can be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients according to conventional techniques such as those disclosed in "Remington: The Science and Practice of Pharmacy", 22nd Edition, Gennaro , Publisher, Mack Publishing Co., Easton, PA, 2013.

[0107] Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solution, and various organic solvents. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, agar, pectin, acacia, stearic acid and lower alkyl ethers of cellulose, corn starch, potato starch, talc, magnesium stearate, gelatin, lactose, gums and the like. Other adjuvants or additives commonly used for such purposes, such as colorings, flavorings, preservatives, etc., may be used, provided they are compatible with the active ingredients.

[0108] Pharmaceutical compositions formed by combining the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy) hydrochloride benzylamine and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration. The formulations can be presented in dosage form by methods known in the field of pharmacy.

[0109] Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules or tablets, each containing a predetermined amount of the active ingredient, and which may include one or more suitable excipients. Orally available formulations may be in the form of a powder or granules, a solution or suspension in an aqueous or non-aqueous liquid, or an oil-in-water or water-in-oil liquid emulsion. If a solid carrier is used for oral administration, the preparation may be tableted, placed in a hard gelatine capsule in powder or pellet form, or may take the form of a troche or lozenge.

[0110] Without limiting the scope of the invention, an example of an immediate release formulation of a daily dose of 30 mg of polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl) hydrochloride Ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine is as follows: N-[2-(6-Fluoro-1H-indol-3-32.75 mg yl)ethyl hydrochloride polymorphic form III ]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine Dibasic Calcium Phosphate 222.0 mg Colloidal Silicon Dioxide NF (Aerosil 200) 3.900 mg Magnesium Stearate NF (Vegetable Grade) 1.300 mg

[0111] The formulation can be encapsulated, for example, in a gelatin capsule of size No. 3.

[0112] Similarly, pharmaceutical compositions comprising the administration of polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2, 3,3-tetrafluoropropoxy)benzylamine wherein the dose ranges administered are between about 5 mg and about 120 mg.

treatment methods

[0113] There is provided herein a combination therapy useful for the treatment of mild, moderate and severe Alzheimer's disease, as well as symptoms associated with mild to moderate Alzheimer's disease. As discussed below, the methods provided herein have several advantages.

[0114] The term "Alzheimer's disease" refers to a progressive disease of the human central nervous system. It manifests as dementia, typically in the elderly, disorientation, memory loss, difficulty with language, calculation or visuospatial skills, and psychiatric manifestations. It is associated with degenerating neurons in various regions of the brain. The term "dementia" as used herein includes, but is not restricted to, Alzheimer's dementia with or without psychotic symptoms.

[0115] In a particular embodiment, the therapeutic methods provided herein are effective for treating mild, moderate, and severe Alzheimer's disease in a subject. Alzheimer's stages additionally include "moderately severe cognitive decline", also called "moderate or intermediate stage Alzheimer's disease"; "severe cognitive decline", also called "moderately severe or intermediate-stage Alzheimer's disease"; and "very severe cognitive decline," also called "severe or advanced-stage Alzheimer's disease." Moderately severe cognitive decline is characterized by severe memory loss and impaired cognitive function. At this stage, some help with everyday activities becomes essential. In severe cognitive decline, difficulties with memory continue to get worse, significant personality changes may develop, and affected individuals may need a lot of help with ordinary everyday activities. Late-stage Alzheimer's disease or very severe cognitive decline is the final stage of the disease when individuals lose the ability to respond to their environment, the ability to speak, and eventually the ability to control movement.

[0116] In another embodiment, the patient to be treated by the combination therapy of the invention has an MMSE score between 12 and 22. "MMSE" refers to the Mini-Mental State Examination ("Mini-Mental State Examination") used in cognitive assessment community.

[0117] In one embodiment, the present invention relates to a method of treating Alzheimer's disease as adjunctive therapy to treatment directed at acetylcholinesterase comprising administering an effective daily dose of polymorphic form III of N-[2-(6) hydrochloride -fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine to a patient in need of such treatment. In an additional embodiment, the effective daily dose administered to the patient of polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3 -tetrafluoropropoxy)benzylamine is between about 5 and about 120 mg. In an additional embodiment, the effective daily dose administered to the patient of polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3 -tetrafluoropropoxy)benzylamine is between about 30 and about 60 mg. In a further embodiment, the acetylcholinesterase inhibitor is donepezil. In a further embodiment, the acetylcholinesterase inhibitor is rivastigmine. In a further embodiment, the acetylcholinesterase inhibitor is galantamine. In a further embodiment, the acetylcholinesterase inhibitor is tacrine.

[0118] In one embodiment, the present invention relates to a method of treating a disease or a disorder selected from dementia in Parkinson's disease, Huntington's chorea and Down syndrome comprising administering an effective daily dose of polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride to a patient in need of such treatment.

[0119] In one embodiment, the present invention relates to a method of treating a disease or a disorder selected from cognitive disorders, age-related cognitive disorder, mild cognitive impairment, mood disorders (including depression, mania, bipolar disorders ), psychosis (in particular schizophrenia), anxiety, panic disorder with or without agoraphobia, agoraphobia without a history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder , generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder, and other unspecified anxiety disorder (particularly including generalized anxiety disorder, panic disorder, and obsessive-compulsive disorder), idiopathic and drug-induced Parkinson's disease, epilepsy, seizures, migraine (including migraine headache), withdrawal (including from substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc. ), sleep disorders (including narcolepsy), attention deficit/hyperactivity disorder, conduct disorder, learning disorders, dementia (including Alzheimer's disease and AIDS-induced dementia), Huntington's chorea, cognitive deficits subsequent to surgery heart failure and bypass graft, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, vascular dementia, multi-infarct dementia, amyotrophic lateral sclerosis and multiple sclerosis comprising administering one dose daily effective dose of polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride to a patient in need of such treatment.

[0120] In one embodiment, the present invention relates to the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3, 3-tetrafluoropropoxy)benzylamine for use in the treatment of Alzheimer's disease as adjunctive therapy to acetylcholinesterase-directed treatment. In an additional embodiment, the dose of polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride is between about 5 and about 120 mg. In an additional embodiment, the dose of polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride is between about 30 and about 60 mg. In a further embodiment, the acetylcholinesterase inhibitor is donepezil. In a further embodiment, the acetylcholinesterase inhibitor is rivastigmine. In a further embodiment, the acetylcholinesterase inhibitor is galantamine. In a further embodiment, the acetylcholinesterase inhibitor is tacrine.

[0121] In one embodiment, the present invention relates to the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3, 3-tetrafluoropropoxy)benzylamine for use in the treatment of a selected disease or disorder of dementia in Parkinson's disease, Huntington's chorea and Down's syndrome.

[0122] In one embodiment, the present invention relates to the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3, 3-tetrafluoropropoxy)benzylamine for use in the treatment of a disease or disorder selected from cognitive disorders, age-related cognitive impairment, mild cognitive impairment, mood disorders (including depression, mania, bipolar disorders), psychosis (in particular schizophrenia) , anxiety, panic disorder with or without agoraphobia, agoraphobia without a history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder and other unspecified anxiety disorder (particularly including generalized anxiety disorder, panic disorder and obsessive-compulsive disorder), idiopathic and drug-induced Parkinson's disease, epilepsy, seizures, migraine (including migraine headache), withdrawal (including from substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), sleep disorders (including narcolepsy) , attention-deficit/hyperactivity disorder, conduct disorder, learning disorders, dementia (including Alzheimer's disease and AIDS-induced dementia), Huntington's chorea, cognitive deficits subsequent to heart surgery and bypass grafting, stroke , cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, vascular dementia, multi-infarct dementia, amyotrophic lateral sclerosis and multiple sclerosis.

[0123] In one embodiment, the present invention relates to the use of polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2, 3,3-tetrafluoropropoxy)benzylamine for the manufacture of a drug for the treatment of Alzheimer's disease as an adjunct therapy to acetylcholinesterase-targeted treatment. In an additional embodiment, the dose of polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride is between about 5 and about 120 mg. In an additional embodiment, the dose of polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride is between about 30 and about 60 mg. In a further embodiment, the acetylcholinesterase inhibitor is donepezil. In a further embodiment, the acetylcholinesterase inhibitor is rivastigmine. In a further embodiment, the acetylcholinesterase inhibitor is galantamine. In a further embodiment, the acetylcholinesterase inhibitor is tacrine.

[0124] In one embodiment, the present invention relates to the use of polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2, 3,3-tetrafluoropropoxy)benzylamine for the manufacture of a medicament for the treatment of a selected disease or disorder of dementia in Parkinson's disease, Huntington's chorea and Down's syndrome.

[0125] In one embodiment, the present invention relates to the use of polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2, 3,3-tetrafluoropropoxy)benzylamine for the manufacture of a medicament for the treatment of a disease or a disorder selected from cognitive disorders, age-related cognitive disorder, mild cognitive impairment, mood disorders (including depression, mania, bipolar disorders), psychosis (in particular schizophrenia), anxiety, panic disorder with or without agoraphobia, agoraphobia without a history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a general medical condition, substance-induced anxiety disorder and other unspecified anxiety disorder (particularly including generalized anxiety disorder, panic disorder, and obsessive-compulsive disorder), Idiopathic and drug-induced Parkinson's, epilepsy, seizures, migraine (including migraine headache), withdrawal (including from substances such as opiates, nicotine, tobacco products, alcohol, benzodiazepines, cocaine, sedatives, hypnotics, etc.), sleep disorders (including narcolepsy), attention-deficit/hyperactivity disorder, conduct disorder, learning disorders, dementia (including Alzheimer's disease and AIDS-induced dementia), Huntington's chorea, cognitive deficits subsequent to cardiac surgery, and heart bypass graft, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemic neuronal damage, vascular dementia, multi-infarct dementia, amyotrophic lateral sclerosis and multiple sclerosis.

EXPERIMENTAL SECTION X-Ray Powder Diffractograms (XRPD)

[0126] X-ray powder diffractograms (XRPD) were measured on a PANalytical X'Pert PRO X-ray diffractometer using CuKα1 radiation. Samples were measured in reflection mode in the 2θ range from 3 to 40° using an X'celerator detector. Diffraction data are displayed ± 0.10 (°2θ).

IR spectra obtained by Fourier transform infrared spectrometry (FTIR)

[0127] Infrared spectra (IR spectra) are recorded on a BRUKER TENSOR 27 FTIR spectrometer equipped with an attenuated total reflectance (ATR) unit with a diamond reflection element. Spectra are obtained using a spectral resolution of 1 cm-1 and 32 scans. The IR bands provided are indicated as ± 1 cm-1.

Example 1: Synthesis of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride

[0128] The synthesis of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride can be found in US patent No. No. 7,157,488, which is hereby incorporated in its entirety by citation. See, for example, column 109, line 1, through column 110, line 3, for a synthesis starting with commercially available 6-fluoroindole.

Example 2: Preparation of polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride

[0129] 6 ml of a solvent or a mixture of solvents are added to a glass vial along with the polymorphic form I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl hydrochloride ]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine. The added amount of compound is determined by the expected solubility in the relevant solvent or solvent system. If a clear solution is obtained, antisolvent and/or more of polymorphic form I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3 hydrochloride) are added. ,3-tetrafluoropropoxy)benzylamine to a suspension at the relevant temperature. The suspension is transformed into a slurry over a long period of time. The result of the slurry experiment is evaluated by removing the solid material by filtration and measuring the XRPD of the isolated solid.

Slurry in a toluene/acetonitrile solvent mixture at 50 °C:

[0130] 6 ml of a solvent mixture of toluene/acetonitrile (4:1) were added to a glass vial and 100 mg of polymorphic form I of N-[2-(6-fluoro-1H-indole hydrochloride) -3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine were added. The resulting suspension was heated to 50 °C. A clear solution was obtained and a further 50 mg was added. The suspension was stirred for one month at 50 °C. Polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride was obtained, as evaluated by XRPD .

Slurry in an acetone/heptane solvent mixture at 50 °C:

[0131] 6 ml of a solvent mixture of acetone/heptane (1:4) were added to a glass vial and 100 mg of polymorphic form I of N-[2-(6-fluoro-1H-indole hydrochloride -3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine were added. The resulting suspension was heated to 50 °C. The suspension was stirred for one week at 50°C. Polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride was obtained, as evaluated by XRPD .

Slurry in a methanol/toluene solvent mixture at 50 °C:

[0132] 6 ml of a solvent mixture of methanol/toluene (1:9) were added to a glass vial and 100 mg of polymorphic form I of N-[2-(6-fluoro-1H-indole hydrochloride) -3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine were added. After stirring, another 1 ml of antisolvent (toluene) + 50 mg of polymorphic form I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2, 2,3,3-tetrafluoropropoxy)benzylamine. Stirring resulted in a clear solution, and 1 ml of toluene and another 50 mg of polymorphic form I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-( 2,2,3,3-tetrafluoropropoxy)benzylamine. Stirring continued to result in a clear solution and the total volume of 8 ml was divided into two. To the 4 ml solutions was added another 1 ml of toluene and another 50 mg of polymorphic form I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2 ,3,3-tetrafluoropropoxy)benzylamine. The resulting suspension was heated to 50 °C. A clear solution was obtained and substance was added until a suspension was obtained. The suspension was stirred for one week at 50°C. Polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride was obtained, as evaluated by XRPD .

Isopropyl acetate slurry at 50 °C:

[0133] 6 ml of isopropyl acetate were added to a glass vial and 50 mg of polymorphic form I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-hydrochloride (2,2,3,3-tetrafluoropropoxy)benzylamine were added. The resulting suspension was heated to 50 °C. A clear solution was obtained and an additional 50 mg of polymorphic form I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy) hydrochloride benzylamine were added. Substance was added until a suspension was obtained at 50 °C. The suspension was stirred for one week at 50°C. Polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride was obtained, as evaluated by XRPD .

Ethyl acetate slurry at 50 °C:

[0134] 6 ml of ethyl acetate were added to a glass vial and 150 mg of polymorphic form I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-hydrochloride (2,2,3,3-tetrafluoropropoxy)benzylamine were added. The resulting suspension was heated to 50 °C on a thermal stirring plate. A clear solution was obtained and 50 mg of polymorphic form I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride have been added. N-[2-(6-Fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride form I was added until a suspension was obtained. . The suspension was stirred for one month at 50 °C. Polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride was obtained, as evaluated by XRPD .

[0135] The polymorphic form I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride is transformed into the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride when slurried at 50 °C. As no solvate is formed, this shows that the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy) hydrochloride benzylamine is less soluble and therefore thermodynamically stable at 50 °C.

Isopropyl acetate slurry at 25 °C:

[0136] 6 ml of isopropyl acetate were added to a glass vial and 50 mg of polymorphic form I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3- hydrochloride (2,2,3,3-tetrafluoropropoxy)benzylamine were added. The suspension was stirred for one month at 25°C. Polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride was obtained, as evaluated by XRPD .

Slurry in dichloromethane at 25 °C:

[0137] 6 ml of dichloromethane were added to a glass vial and 50 mg of polymorphic form I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3- hydrochloride (2 ,2,3,3-tetrafluoropropoxy)benzylamine were added. The suspension was stirred for one month at 25°C. Polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride was obtained, as evaluated by XRPD .

Slurry in 2-butanol at 25 °C:

[0138] 6 ml of 2-butanol were added to a glass vial and 100 mg of polymorphic form I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-hydrochloride (2,2,3,3-tetrafluoropropoxy)benzylamine were added. The suspension was stirred for one month at 25°C. Polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride was obtained, as evaluated by XRPD .

[0139] The polymorphic form I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride is transformed into the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride when slurried at 25 °C. As no solvate is formed, this shows that the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy) hydrochloride benzylamine is less soluble and therefore thermodynamically stable at 25 °C.

Slurry in a methanol/toluene solvent mixture at 5 °C:

[0140] 6 ml of a solvent mixture of methanol/toluene (1:9) were added to a glass vial and 100 mg of polymorphic form I of N-[2-(6-fluoro-1H-indole hydrochloride) -3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine were added. After stirring, another 1 ml of antisolvent (toluene) + 50 mg of polymorphic form I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2, 2,3,3-tetrafluoropropoxy)benzylamine. Stirring resulted in a clear solution, and 1 ml of toluene and another 50 mg of polymorphic form I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-( 2,2,3,3-tetrafluoropropoxy)benzylamine. Stirring continued to result in a clear solution and the total volume of 8 ml was divided into two. To the 4 ml solutions was added another 1 ml of toluene and another 50 mg of polymorphic form I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2 ,3,3-tetrafluoropropoxy)benzylamine. The saturated supernatant together with a small amount of solid from the suspension obtained was transferred to a glass vial and stirred in the refrigerator at 5 °C for three months. Polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride was obtained, as evaluated by XRPD .

[0141] The polymorphic form I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride is transformed into the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride when slurried at 5°C. As no solvate is formed, this shows that the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy) hydrochloride benzylamine is less soluble and therefore thermodynamically stable at 5 °C.

Example 3: Preparation of polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride by seeding

[0142] Polymorphic form I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride (3858 g) in a mixture of acetonitrile (4.55 kg) and toluene (5 kg) was heated to 80 °C to obtain a clear solution. The solution was then cooled to 45 °C before being seeded with polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3 ,3-tetrafluoropropoxy)benzylamine (4.8 g) and then further cooled to 42 °C. After 18 hours, a portion of toluene (7.2 kg) was added, followed by a further portion of toluene (16.7 kg) and the solution was stirred at about 45 °C for 3 days, cooled and filtered to to give polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride which was washed with toluene ( 3.9 kg). The compound was dried to give polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride ( 3.722 kg).

[0143] Polymorphic form I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride (40 g) in toluene (480 ml) under a nitrogen atmosphere was heated to 110 °C before being slowly cooled to 52 °C. The suspension was then seeded with polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride and shaken overnight. A small sample of the suspension was removed, cooled and filtered; the solid obtained was analyzed by XRPD and identified as being the polymorphic form II of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3- tetrafluoropropoxy)benzylamine. The temperature of the suspension was lowered to 45 °C before being seeded with polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2, 3,3-tetrafluoropropoxy)benzylamine and stirred overnight. A small sample of the suspension was removed, cooled and filtered; the solid obtained was analyzed by XRPD and identified as being the polymorphic form II of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3- tetrafluoropropoxy)benzylamine. The suspension at 45 °C was seeded with polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy) hydrochloride benzylamine and stirred for two days. A small sample of the suspension was removed, cooled and filtered; the solid obtained was analyzed by XRPD and identified as being a mixture of polymorphic forms II and III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2, 3,3-tetrafluoropropoxy)benzylamine. The temperature of the suspension was lowered to 40°C before being seeded with polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2, 3,3-tetrafluoropropoxy)benzylamine and stirred overnight. A small sample of the suspension was removed, cooled and filtered; the solid obtained was analyzed by XRPD and identified as being a mixture of polymorphic forms II and III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2, 3,3-tetrafluoropropoxy)benzylamine. Acetonitrile (50 ml) was added before the suspension was seeded with polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3 ,3-tetrafluoropropoxy)benzylamine and stirred overnight at 40 °C. A small sample of the suspension was removed, cooled and filtered; the solid obtained was analyzed by XRPD and identified as being the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3- tetrafluoropropoxy)benzylamine with traces of the polymorphic form I.

[0144] Polymorphic form I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride (40 g) in Isopropyl acetate (480 ml) under a nitrogen atmosphere was heated to 81 °C to give a clear solution before it was slowly cooled to 50 °C and subsequently seeded with the polymorphic form III of N-[2- (6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine and stirred overnight. A small sample of the suspension was removed, cooled and filtered; the solid obtained was analyzed by XRPD and identified as being the polymorphic form II of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3- tetrafluoropropoxy)benzylamine with traces of polymorphic form I or III. The temperature of the suspension was lowered to 45 °C before being seeded with polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2, 3,3-tetrafluoropropoxy)benzylamine and stirred overnight. A small sample of the suspension was removed, cooled and filtered; the solid obtained was analyzed by XRPD and identified as being the polymorphic form II of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3- tetrafluoropropoxy)benzylamine with traces of polymorphic form I or III. The suspension at 45 °C was seeded with polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy) hydrochloride benzylamine and stirred for three days. A small sample of the suspension was removed, cooled and filtered; the solid obtained was analyzed by XRPD and identified as being the polymorphic form II of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3- tetrafluoropropoxy)benzylamine with traces of the polymorphic form I/III. The suspension at 45 °C was seeded with polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy) hydrochloride benzylamine and stirred for six days. A small sample of the suspension was removed, cooled and filtered; the solid obtained was analyzed by XRPD and identified as being the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3- tetrafluoropropoxy)benzylamine. The solution was cooled to 5 °C and isolated by filtration, dried under reduced pressure to give polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-hydrochloride (2,2,3,3-tetrafluoropropoxy)benzylamine (37.6 g).

[0145] Heating the polymorphic form I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride in toluene as described above will result in the formation of polymorphic form II upon cooling from 110 °C, as polymorphic form II is the most stable at temperatures above 60 °C, and more easily formed than polymorphic form III. By lowering the temperature and adding acetonitrile to the slurry, thus achieving greater solubility, the polymorphic form III was obtained. Traces of polymorphic form I could be obtained by evaporating the solvent during filtration, indicating that polymorphic form I is more easily formed at low temperatures compared to polymorphic form III.

[0146] Polymorphic form I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride (49 g) in a mixture of acetonitrile (74 ml) and toluene (74 ml) was heated to 84°C to obtain a clear solution under a nitrogen atmosphere. The solution was slowly cooled to 45°C over about 1 hour before being seeded with polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3 hydrochloride -(2,2,3,3-tetrafluoropropoxy)benzylamine (100 mg) and stirred at 41 to 43 °C for about 1.5 hours. Toluene (200 ml) was slowly added maintaining the temperature between 40 and 43 °C. The suspension was then slowly warmed to 50°C and stirred at that temperature for 17 hours. The suspension was then slowly cooled to 31°C and filtered and washed with a mixture of toluene (162 ml) and acetonitrile (18 ml). The compound was dried to give polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride ( 44.8g).

Example 4: Evaporative crystallization experiments

[0147] 4.5 ml of ethyl acetate and 45 mg of polymorphic form I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3 hydrochloride) ,3-tetrafluoropropoxy)benzylamine were added to a glass vial and stirred for a few minutes to obtain a clear solution. The solution was divided into three.

[0148] 1/3 of the solution was kept at 25 °C, without a lid, for faster evaporation, resulting in the polymorphic form I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl hydrochloride ]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine.

[0149] 1/3 of the solution was kept at 50 °C, without a lid, for faster evaporation, resulting in the polymorphic form II of N-[2-(6-fluoro-1H-indol-3-yl)ethyl hydrochloride ]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine.

[0150] 1/3 of the solution was kept at 50 °C, with a lid with a small hole, for slow evaporation, resulting in the polymorphic form II of N-[2-(6-fluoro-1H-indole-3 hydrochloride) -yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine.

[0151] 3 ml of a solvent mixture of 2-butanone/heptane (1:4) and 45 mg of polymorphic form I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl hydrochloride ]- 3-(2,2,3,3-tetrafluoropropoxy)benzylamine were added to a glass vial and stirred for a few minutes resulting in a suspension. 1 ml of 2-butanone was added but solid material was still observed. 1 ml of the solution was removed and 1 ml of 2-butanone was added and a clear solution was obtained. The solution was divided into three.

[0152] 1/3 of the solution was kept at 25 °C, without a lid, for faster evaporation, resulting in the polymorphic form I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl hydrochloride ]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine.

[0153] 1/3 of the solution was kept at 50 °C, without a lid, for faster evaporation, resulting in the polymorphic form II of N-[2-(6-fluoro-1H-indol-3-yl)ethyl hydrochloride ]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine.

[0154] 1/3 of the solution was kept at 50 °C, with a lid with a small hole, for slow evaporation, resulting in the polymorphic form I of N-[2-(6-fluoro-1H-indole-3 hydrochloride) -yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine.

[0155] Evaporation of the solvent from a solution of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride at 25 °C and 50 °C results in the formation of polymorphic forms I and II, but not polymorphic form III. The results of these experiments indicate that the polymorphic forms I and II of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride have a kinetic advantage over the polymorphic form III which is the thermodynamically stable form at these temperatures.

Example 5: Relative stability of polymorphic forms I, II and III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy) hydrochloride benzylamine

[0156] A saturated solution was prepared by heating 1.6 ml of isopropyl acetate and 0.4 ml of heptane to 70 °C and adding 50 mg of polymorphic form I of N-[2-(6- fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine. On stirring for two hours and then standing without stirring at 70°C overnight, a saturated solution was obtained in which solid material was visible.

[0157] The supernatant was divided into two ampoules and kept at 60 °C and 70 °C.

[0158] 5 mg of polymorphic forms I, II and III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy) hydrochloride benzylamine were added to the solution at 60 °C and kept under stirring at 60 °C for one and four days, respectively. Evaluation after one day resulted in a mixture of polymorphic forms II and III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3- tetrafluoropropoxy)benzylamine and the polymorphic form I disappeared. Evaluation after four days resulted in the polymorphic form II of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride and traces of the polymorphic form III.

[0159] 2.5 mg of polymorphic forms I, II and III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3- tetrafluoropropoxy)benzylamine were added to the solution at 70°C and kept without stirring at 70°C for three days. The evaluation resulted in the polymorphic forms II and I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride and the form polymorph III disappeared.

[0160] The polymorphic forms I, II and III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride were mixed in equal amounts and slurried in isopropyl acetate at 60 °C. After one day it is just a mixture of polymorphic forms II and III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy) hydrochloride benzylamine and the polymorphic form I disappeared. After four days, it is observed that the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride is transforming into the polymorphic form II. This shows that polymorphic form I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride is less stable than polymorph form III and polymorph form II are thermodynamically stable at that temperature. The fact that the transformation is slow indicates that it is close to the transition temperature between the polymorphic forms II and III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2, 2,3,3-tetrafluoropropoxy)benzylamine. At 70 °C the transformation is faster and a suspension of equal amounts of polymorphic forms I, II and III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-( 2,2,3,3-tetrafluoropropoxy)benzylamine kept without stirring will transform into the polymorphic form II within three days. This shows that the polymorphic form II of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride is thermodynamically stable at 70 °C.

Example 6: Solubility in organic solvents

[0161] The thermodynamic solubility of polymorphic forms I and III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride was measured by stirring an excess amount of the two polymorphic forms in the organic solvent in a sealed vessel at room temperature (about 23 °C). After reaching equilibrium, a sample was taken, the solid separated by filtration or centrifugation, and the clear filtrate/supernatant evaluated by HPLC at 217 nm. The precipitate was evaluated by XRPD to determine the polymorphic form. Table 2: Solubility of polymorphic forms III and I of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride in solvents organic.

[0162] The solubility experiments in organic solvents show that the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3 -tetrafluoropropoxy)benzylamine is slightly less soluble and therefore thermodynamically stable at room temperature (about 23 °C).

Example 7: Preparation of a mixture of polymorphic form III and polymorphic form IV.

[0163] A saturated solution of ethanol and polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy) hydrochloride benzylamine is prepared at room temperature. The slurry is allowed to equilibrate under constant agitation. A small sample of the slurry containing liquid and solid material is drawn off with a pipette and allowed to evaporate.

[0164] A mixture of polymorphic form III and polymorphic form IV of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy hydrochloride) )benzylamine was obtained, as evaluated by XRPD (figure 7).

[0165] The characteristic peaks of XRPD of the polymorphic form IV are shown below (±0.10 (°2θ)):

[0166] 17.52, 17.73, 19.20, 19.72, 20.30, 21.60, 23.07, 23.87, 26.41.

Example 8: FTIR spectra of polymorph form III and polymorph form I.

[0167] The IR spectra of polymorphic form I and polymorphic form III were recorded as described above. Table 3: The positions and relative intensity of the FTIR bands for polymorphic form I and polymorphic form III.

Claims (17)

1. Compound, characterized by the fact that it is the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy) hydrochloride benzylamine which features an X-ray powder diffractogram showing peaks at the following 2θ angles: 4.63°, 6.94°, 13.89°, 17.26°, 18.07°, 18.49°, 18 .95°, 19.47°, 19.97°, 20.53°, 21.83°, 22.53°, 23.27°, 23.65° and 28.91°. 2. Compound according to claim 1, characterized in that it is the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2, 3,3-tetrafluoropropoxy)benzylamine which features an FTIR spectrum that has a strong relative band intensity at the following band positions [cm-1]: 3426, 1586, 1089, 762 and a shoulder at 1099 cm-1. 3. Compound according to claim 1 or 2, characterized in that it is for use as a medicine. 4. Compound according to any one of claims 1 to 3, characterized in that it is for use in the treatment of Alzheimer's disease as adjuvant therapy for treatment directed at acetylcholinesterase. 5. Compound according to claim 4, characterized in that the dose is between about 30 and about 60 mg. 6. Process for preparing the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride defined in claim 1, characterized by the fact that it comprises: a. stir a suspension of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride in an organic solvent selected from the list of acetonitrile , propionitrile, acetone, methanol, ethanol, heptane, toluene and xylenes (ortho, meta or para) or a mixture thereof, at a temperature below 60 °C; and b. capturing the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride. 7. Process for preparing the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride defined in claim 1, characterized by the fact that it comprises: a. add polymorphic form I, polymorphic form II, amorphous form or a mixture of forms of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2, 3,3-tetrafluoropropoxy)benzylamine to an organic solvent selected from the list of acetonitrile, propionitrile, acetone, methanol, ethanol, heptane, toluene and xylenes (ortho, meta or para) or a mixture thereof, at a temperature below 60 °C to produce a suspension and stir the suspension; and b. capturing the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride. 8. Process for preparing the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride defined in claim 1, characterized by the fact that it comprises: a. seed a suspension of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride in an organic solvent selected from the list of acetonitrile , propionitrile, acetone, methanol, ethanol, heptane, toluene and xylenes (ortho, meta or para) or a mixture thereof, at a temperature below 60 °C, with the polymorphic form III of N-[2-(6 -fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine; B. capturing the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride. 9. Process for preparing the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride defined in claim 1, characterized by the fact that it comprises: a. add polymorphic form I, polymorphic form II, amorphous form or a mixture of forms of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2, 3,3-tetrafluoropropoxy)benzylamine to an organic solvent selected from the list of acetonitrile, propionitrile, acetone, methanol, ethanol, heptane, toluene and xylenes (ortho, meta or para) or a mixture thereof, at a temperature below 60 °C to produce a suspension; B. seed with polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride at a temperature below 60°C °C; w. capturing the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride. 10. Process according to any one of claims 6 to 9, characterized in that the organic solvent is a mixture of acetone and heptane in the ratio of 1:4. 11. Process according to any one of claims 6 to 9, characterized in that the organic solvent is a mixture of methanol and toluene in the ratio of 1:4. 12. Process according to any one of claims 6 to 9, characterized in that the suspension is produced in the temperature range of 45 °C to 55 °C. 13. Pharmaceutical composition, characterized in that it comprises a compound defined in claim 1 or 2. 14. Pharmaceutical composition according to claim 13, characterized in that it is prepared from the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-( 2,2,3,3-tetrafluoropropoxy)benzylamine, wherein the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3 ,3-tetrafluoropropoxy)benzylamine features an X-ray powder diffractogram showing peaks at the following 2θ angles: 4.63°, 6.94°, 13.89°, 17.26°, 18.07°, 18. 49°, 18.95°, 19.47°, 19.97°, 20.53°, 21.83°, 22.53°, 23.27°, 23.65° and 28.91°. 15. Pharmaceutical composition according to claim 13, characterized in that it is prepared from the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-( 2,2,3,3-tetrafluoropropoxy)benzylamine, wherein the polymorphic form III of N-[2-(6-fluoro-1H-indol-3-yl)ethyl]-3-(2,2,3 ,3-tetrafluoropropoxy)benzylamine features an FTIR spectrum that has a strong band intensity at the following band positions [cm -1 ]: 3426, 1586, 1089, 762 and a shoulder at 1099 cm -1 . 16. Use of a compound defined in claim 1 or 2, characterized in that it is for the manufacture of a drug for the treatment of Alzheimer's disease as an adjuvant therapy for treatment directed at acetylcholinesterase. 17. Use according to claim 16, characterized in that the dose of said compound is between about 30 and about 60 mg.